biostudies-literatureGan PNHLBI NIH HHSNIAMS NIH HHSNIGMS NIH HHSeadk7160https://www.ebi.ac.uk/biostudies/studies/S-EPMC10942106biostudies-literatureUnknown10(11)During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here, we show that the cardiovascular transcriptional coactivator myocardin (MYOCD) activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The carboxyl-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region's ability to form condensates disrupts gene activation and smooth muscle cell reprogramming. Rescuing condensate formation by replacScience advancesCoactivator condensation drives cardiovascular cell lineage specification.PMC10942106R01 AR071980R01 GM147583R01 HL130253R01 HL157281Xu LEppert MChen KLiu NBezprozvannaya SVeettil RTLyons HSabari BRPradhan PGan PShah AMDe La Cruz NOlson ENfalseCoactivator condensation drives cardiovascular cell lineage specification.During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here, we show that the cardiovascular transcriptional coactivator myocardin (MYOCD) activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The carboxyl-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region's ability to form condensates disrupts gene activation and smooth muscle cell reprogramming. Rescuing condensate formation by replac2024-01-01T00:00:00Z2024 Mar2026-07-15T08:25:22.902Z2025-04-06T17:25:06.122ZS-EPMC109421063848935810.1126/sciadv.adk7160